Low molecular weight gels are formed via the self-assembly of low molecular weight gelator (LMWG) molecules with solubility playing a key role.1 Initially, a LMWG must be soluble in a solvent. To begin the self-assembly process, a trigger must be applied. This trigger will decrease the solubility of the LMWG, hence starting the self-assembly process. When the trigger is applied and solubility decreased, the LMWG molecules begin to form fibres. These fibres grow and entangle or cross-link, trapping the solvent to give a self-supporting gel.2 There are many types of trigger including temperature switch and the addition of an enzyme. In our group, we focus mainly on pH, salt and solvent triggered gels.
pH Triggered Gels
For LMWGs with a free carboxylic acid present, a pH switch can be used to trigger gelation. The LMWG is suspended in water and base used to deprotonate the free carboxylic acid, and take the pH of the resulting solution to above the apparent pKa of the gelator. This gives the carboxylate form of the LMWG and makes the LMWG soluble. To trigger this solution into a gel, an acid is added to the LMWG solution. The free carboxylic acid is re-protonated, the solubility of the gelator is decreased, and the LMWG begins to self-assemble to give a gel.3, 4
Different acids can be used as pH triggers. For example, HCl can be utilised in the gelation process, however this relies on diffusion of the acid throughout the sample and does not give reproducible gels.5, 6 We commonly use glucono-δ-lactone (GdL) as a pH trigger.3-5, 7-9 Unlike HCl, which normally does not give homogeneous gels, GdL slowly produces acid to give homogeneous gels. GdL is a sugar with a ring structure which hydrolyses in water and releases protons. These protons can then re-protonate the LMWG. The rate of hydrolysis is slower than the rate of GdL mixing in the solution. Hence, we get an even distribution of protons throughout the sample, resulting in a homogeneous gel.5
We have also shown we can use a photoacid generator (PAG) as a pH switch to form gels. We have previously used the PAGs diphenyliodonium nitrate (DPIN) and 2-(4-methoxystyryl)4,6-bis(trichloromethyl)-1,3,5-triazine (MBTT).10, 11 A PAG can be added to a gelator stock solution and produces acid when exposed to light. This acid can then re-protonate the gelator, decreasing the solubility to give a gel. An advantage of using a PAG to trigger gelation is that the gelation can be selective. By introducing a photomask and blocking UV radiation to sections of the sample, we can control where gelation occurs and form gels of various stiffness in a single sample. However, not all gelators can be triggered using this method. For example, the LMWG 2NapFF can be gelled using MBTT but not DPIN.10, 11
How do we use GdL to make gels?
If, for example, we wish to make a gel with a concentration of 10 mg/mL LMWG triggered using GdL we begin by making a stock solution using a LMWG, 0.1 M NaOH and water. We use one molar equivalent of 0.1 M NaOH to deprotonate our LMWG and the final volume is made up with water. Water should be added before NaOH to reduce the risk of the LMWG breaking apart upon the addition of base. This solution should be stirred overnight until a homogeneous solution is observed. Next, we take a 2 mL aliquot from our stock solution and add it to a pre-weighed mass of GdL in a Sterilin vial. The GdL is gently stirred into the solution and left undisturbed overnight to allow the gel to form. The concentration of GdL used affects the kinetics of formation and the final pH of the gel.3 Enough GdL is required such that the final pH of the gel is below the apparent pKa of the LMWG.
Salt Triggered Gels
Metal ions from salts can be used to trigger self-assembly. For LMWGs that form worm-like micelles in solution and have a free carboxylic acid present, metal ions can be used to cross-link fibres. Similarly to a pH triggered gel, the LMWG is suspended in water and base used to deprotonate the free carboxylic acid. This gives the carboxylate form of the LMWG and makes the LMWG soluble. To trigger this solution into a gel, a salt can cross-link the carboxylates together, reducing the solubility of the LMWG and allowing self-assembly to occur.12, 13 Varying the metal ion affects the properties of the gel, as does the concentration of metal ion used.12 Our group commonly uses the divalent cation from calcium chloride or calcium nitrate to cross-link worm-like micelles and form gels.12-14
How do we use calcium ions to make gels?
If, for example, we wish to make a gel with a concentration of 10 mg/mL LMWG triggered using calcium chloride we begin by making a stock solution (the same as described for pH triggers) using a LMWG, 0.1 M NaOH and water. We use one molar equivalent of 0.1 M NaOH to deprotonate our LMWG and the final volume is made up with water. Water should be added before NaOH to reduce the risk of the LMWG breaking apart upon the addition of base. This solution should be stirred overnight until a homogeneous solution is observed. Next, we take a 2 mL aliquot from our stock solution and add it to a Sterilin vial. Using an aqueous solution of calcium chloride or calcium nitrate, a small aliquot (in the range of 10 µL depending on the concentration of calcium chloride/nitrate solution) is pipetted on top of the solution in the Sterilin vial so that the molar ratio of LMWG to calcium ions is 1:2.14 This is then left undisturbed overnight to allow diffusion of the calcium ions and the gel to form.
Solvent Triggered Gels
A solvent triggered gel requires a solvent and anti-solvent. The solvent is organic and water-miscible and the LMWG must be soluble in it. The anti-solvent acts as the trigger. The LMWG is soluble in the solvent, but when the anti-solvent is added, the solubility of the LMWG molecules decrease and self-assembly begins, eventually giving a gel. The ratio of solvent to anti-solvent can be varied which can alter the final stiffness and microstructure of the gels, and whether or not a gel will form at all.15 Our group commonly uses DMSO as a solvent with water as an anti-solvent.9, 15, 16
How do we use solvent switches to make gels?
If, for example, we wish to make a gel with a concentration of 10 mg/mL LMWG and 20 % DMSO ratio and triggered using a solvent trigger, we use our selected LMWG, DMSO and water. For a 2 mL gel, 20 mg of LMWG is weighed directly into a Sterilin vial and dissolved in 0.4 mL of DMSO. Once dissolved, 1.6 mL of water is quickly pipetted into the LMWG/DMSO solution to give the desired 2 mL final volume with a 20 % ratio of DMSO. The sample is left undisturbed overnight to allow the gel to form.
Large stock solutions at high concentration of LMWG can be prepared using DMSO and LMWG. This can then be diluted with water to still give the desired LMWG concentration and solvent to anti-solvent ratio.
References
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16. A. M. Fuentes-Caparrós, K. McAulay, S. E. Rogers, R. M. Dalgliesh and D. J. Adams, Molecules, 2019, 24, 3855.
Dave Adams Lab 